In order to use a microsphere as a drug delivery system, it is important to design a formulation so as to maximize the therapeutic efficacy of a drug, enhance a patient's compliance against the drug and minimize the side effects thereof by efficiently delivering the drug to a target site to be treated. In particular, a microsphere for drug delivery using a biodegradable polymer should have the capability of introducing a lipid-soluble or a water-soluble biologically active material as a drug thereinto and the physical property capable of holding and maintaining the drug for a certain period of time within the body. Further, such a microsphere should satisfy a number of criteria for successful use as a drug delivery system, e.g., the stability of being degraded into harmless materials to a human body and the durability that it does not release the drug in early stage immediately after administration and, after being delivered to a target site, can sufficiently release the drug for a desirable period. Since the microsphere has a small particle size of 1 to 500 μm, it can be easily administered to a human body by using a conventional syringe. Further, it has the advantage of maintaining the therapeutic efficacy of a drug for a relatively long period of time with only a single administration. Thus, research on microspheres for drug delivery has been actively underway, but microspheres which satisfy properties, such as effective drug encapsulation, initial drug release (burst) control, homogeneous size distribution and the like, have still not been found.
Biodegradable polymers widely used in the art include polyglycolic acid (PGA), polylactic acid (PLA), lactic acid-glycolic acid copolymer (PLGA), poly-ε-caprolactone (PCL), lactic acid-ε-caprolactone copolymer (PLCL), polydioxanone (PDO), polytrimethylene carbonate (PTMC), poly(amino acid), polyanhydride, polyorthoester and copolymers thereof. However, only PGA, PLA, and PLGA have been approved by the FDA as biodegradable polymers available for use in human body, and used as drug delivery microspheres and porous polymer scaffolds for tissue regeneration.
There are several known methods for preparing microspheres by using such a biodegradable polymer, for example, a solvent evaporation-drying method (U.S. Pat. No. 4,652,441), a phase-separation method (U.S. Pat. No. 4,675,189), a spray-drying method (U.S. Pat. No. 6,709,650), a low temperature solvent extraction method (U.S. Pat. No. 5,019,400) and the like. Recently, a method of improving biocompatibility and drug encapsulation efficiency of a microsphere by using a water-soluble organic solvent, such as acetic acid, lactic acid, acetone and the like instead of dichloromethane or chloroform, for dissolving a biodegradable polymer has been reported (U.S. Pat. No. 5,100,699). However, the above methods are problematic in that they can only prepare nonporous microspheres, that they are very complicated and time-consuming, and that the prepared nonporous microspheres release drugs at a very low speed.
As for methods of preparing porous microspheres, the salt infusion/gas foaming method and the phase-separation method using a solvent/non-solvent combination are known. The former is a method of providing a microsphere with porosity by using an effervescent agent such as ammonium bicarbonate (NH4HCO3) (Kim et al., Biomaterials 27: 152-159, 2006), and the latter is a method of providing a microsphere with porosity by using a non-solvent material which is miscible with a solvent used for dissolving a polymer but is immiscible with the polymer (Hong et al., Polym. Adv. Technol. 16: 622-627, 2005). Thus prepared porous microspheres are intended to be used as a cell scaffold for tissue regeneration. So, if they are used for drug delivery, because of the larger surface area due to their high porosity, they may be problematic in that the drug encapsulated in the porous microsphere may be entirely released in the early stage immediately after administration, limiting their use for drug delivery.
Meanwhile, hydrogen peroxide (H2O2) is a safe, effective, powerful and versatile oxidant. Hydrogen peroxide dissolves well in water, ethanol, ether, and the like and is easily degraded into oxygen and water via a catalytic reaction of inorganic materials, such as alkali metals, heavy metals and manganese dioxide, and enzymes such as catalase, and is thus known as an eco-friendly compound. Hydrogen peroxide has been used for a wide variety of industrial applications, such as disinfectants, antiseptics, the bleaching and disinfection of pulps, papers and foods, teeth whitening, agriculture, pollution treatment, propellents of a rocket, and the like. However, there have been no reports on the use of hydrogen peroxide for providing a polymer microsphere with porosity.
The present inventors have therefore studied to prepare biodegradable polymer microspheres which have the advantages of both porous and nonporous microspheres, and found that if a hydrogen peroxide-containing compound is used as an effervescent (foaming) agent for the preparation of a biodegradable polymer microsphere, it is possible to prepare a covered porous biodegradable polymer microsphere that has an interconnected inner open pore structure having a wide surface area and high porosity and an outer closed pore structure in which the surface of the microsphere is covered with a thin layer of a biodegradable polymer, whereby the pores exposed to the outside are closed. The covered porous biodegradable polymer microsphere according to the present invention can effectively control the release of biologically active materials in the early stage immediately after administration, and after that, gradually release the same over a prolonged period as the biodegradable polymer thin film covered on the surface is degraded within the body.